19-halo pregnane derivatives



United States Patent ffice 3,186,988 Patented June 1, 1965 3,186,988 19-HALO PREGNANE DERIVATIVES Albert Bowers, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing; Filed Dec. 6, 1963, Ser. No. 328,474 Claims priority, applicggitgiglexico, Feb. 19, 1962,

29 Claims. (31. 260-23955) In the above formulae R represents hydrogen, hydroxy or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T represents hydrogen, a-hydroxy, uacyloxy, e-methyl or fi-rnethyl; T and R together represent the group in the 16a,l7a-position, wherein R and R each represent hydrogen or a lower hydrocarbon residue of up to 8 carbon atoms, which may be saturated or unsaturated, of straight branched, cyclic or mixed aliphatic cyclic chain, or aromatic, such as methyl, ethyl, isopropyl, phenyl, toluyl, methyl-cycloh'exyl and the like; X represents iluorine or chlorine; Z represents hydrogen, methyl, fluorine or chlorine, all having a: or B configuration; and W represents a double bond or a saturated linkage between C-1 and C-2.

The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and fi-chloropropionate.

The compounds represented by the above formulae are powerful progestational agents with good oral activity.

In addition, they have anti-androgenic, anti-gonadotrophic' and anti-estrogenic properties, are very useful in fertility control and are devoid of androgenic activity. Furthermore, they may be used in the treatment of premenstrual tension and exhibit blood cholesterol lowering and diuretic activities. When applied topically, these compounds are very useful in the treatment of acne.

The novel compounds of the present invention are prepared by the process illustrated by the following equation:

a a t IT a m l l (Id) 1 ll/ CH:

11;; ii] if 1Q ifb 1 0-.

1 1 ii] L I M if! Z a (V) (IV) in .olk/

In the above formulae R, T, X and Z have the same meaning as previously described; R represents hydrogen or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T may be hydrogen, u-acyloxy, u-methyl or fi-methyl; T and R together represent the group (VIII) wherein R and R have the same meaning as set forth hereinbefore; and 1 indicates that'the 19-carbon may be at aor ii-configuration.

The starting compounds of the present process represented by Formula I, which is a A -a-pregnen-19-ol- 3,20-dione derivative, is obtained according to Cross, U.S. patent application Serial No. 231,831, filed October 19, 1962, from the corresponding A -pregnen-19-ol-3,20- dione, by hydrogenation of the A -double bond, tosylation of the resulting allopregnan-l 9-ol-3,20'dione treatment of the obtained 19-tosylate with sodium hydride, hydrolysis of the resulting 2,l9-cyclo-allopregnane-3,20- dione in a strong acid or basic medium and finally introduction of a A -double bond-into the obtained 10ccallopregnan-19-ol-3,20-dione by conventional procedures, i.e. successive treatment with bromine, sodium iodide and 'y-collidine.

The starting compound of the present process represented by formula Ia, which is a l9-halo-A -pregnen-3j3- ol-20-one is obtained in accordance with my U.S. patent application Serial No. 194,717, filed May 14, 1962, by treating the corresponding A -pregnene-3p,19-diol-20-one 3-acetate with a fluorinating agent such as 2-chloro-l,1,2- trifluorotriethylamine or with tosyl chloride followed by a lithium halide and, thereafter, by saponification with a base such as aqueous methanolic potassium hydroxide.

In carrying out the process just outlined, the starting compound of the type represented by Formula I is treated with approximately 1 molar equivalent of tosyl chloride in pyridine, thus giving the corresponding 19-tosylate, which upon treatment with an alkali metal fluoride or chloride, such as lithium fluoride or chloride, yields the 4 corresponding 19-fluoro or chloro-A -10a-pregnene 3,20 dione (II; i=0).

When starting with a compound of the type'represented by formula Ia, the latter is treated under conventional Oppenauer conditions to produce the corresponding 19- halo-A -pregnene-S,20-dione (Hi-=18).

The 19-halo-A -pregnene-3,ZO-dione derivative (II) having either 100: or 10,3 configuration upon reaction with ethylene glycol in the presence of p-toluenesulfonic acid yields the corresponding 3,20-bis-cycloethylenedioxy-19- halo-A -pregnene derivatives (III).

The latter compound upon treatment with an organic peracid, such as monoperphthalic acid in an inert solvent, preferably chloroform, yields the corresponding 3,20-biscycloethylenedioxy-5u,6a-oxido-l9-halo-pregnane (IV);

Upon reaction of the latter 3,ZO-bis-cycloethylenedioxy- 50:,6oc-OXld0 compound with methyl magnesium bromide in an inert solvent, such as ether of tetrahydrofuran, followed by conventional working up and treatment of the residue with a mineral acid, such as 8% sulfuric acid, and thereafter with an alkali metal hydroxide, such as sodium hydroxide, there is obtained the corresponding" 19-halo-6a-methyl A pregnene 3,20 dione derivative (V: Z=a-methyl).

When treating the 3,ZO-bis-cycloethylenedioxy-5a,6aoxido compounds (IV) with anhydrous hydrogen chloride in a suitable solvent, such as ethyl acetate, there are produced the corresponding Got-chloro-19-halo-A -pregnene- 3,20-dione derivatives (V: Z=a-chlorine-).

Upon reaction of the 3,20*bis-cycloethylenedioxy- 5a,6a-0Xid0 compounds (IV) with anhydrous hydrogen fluoride in the presence of boron trifluoride etherate, followed by treatment with hydrogen chloride, there are produced the corresponding 6a-fluoro-19-halo-A -pregnene-3,20-dione derivatives ,(V: Z=a-fluorine).

Upon treating a 3,20-bis-cycloethylenedioxy-5a,6aoxido derivative (IV) with methyl magnesium bromide in an inert solvent, such as ether or tetrahydrofuran, the resulting steroid reacted with 8% sulfuric acid and'worked up conventionally, thereaftertreated with thionyl chloride in pyridine at about --'10.C., for approximately 4 minutes, thus affording the corresponding l9-halo-6B-methyl- A -pregnene-3,20-dione derivative (V: Z=,6-methyl).

The 19-halo-A -pregnene-3,20-dione derivatives (II) are treated with ethyl orthoformate in the presence of p-toluenesulfonic acid and in an inert solvent, thus aifordingthe corresponding 19-halo-3-eth0xy-A pregnadien-20-one derivatives which upon reaction with approximately 1 molar equivalent of N-chloro-succinimide or another N-chloro amide or imide, in the presence of sodium ace tate and acetic acid, yield the corresponding 6,8-chloro- 19-halo-A -pregnene-3,ZO-dione (V: Z=fl-chlorine).

The aforementioned 19-halo-3-ethoxy-A -pregnadien- 20-one derivatives are treated with perchloryl fluoride in dimethylformamide to produce the corresponding 6}?- fluoro-19-halo-A -pregnene-3,20-dione derivatives (V: Z=fl-fluorine) The Got-halo compounds of the present invention (V: Z=a-halogen) may also be obtained by treatment of the corresponding 6p halo compounds (V: Z=,6-'ha1ogen') with hydrogen-chloride in aceticacid, or with any other mixture with similar acidity.

The 19-hal0-A '-pregnene-3,ZO-dione derivatives (V) are treated with 2,3-dichloro-5,6-dicyano-l,4 benzoquinone in an inert solvent, such as dioxane, preferably at refiux'tem perature, for a period of time of the'order of 10' hours to produce the corresponding 19-halo-A -pregnadiene- 3,20-dione compounds (VI).

The 19-halo-A -pregnene-3,ZO-dione derivatives (V) upon treatment with ethyl orthoformate in an inert solvent and in the presence of p-toluenesulfonic acid furnish'the corresponding 19-halo-3-ethoxy-A -pregnadiene derivatives, which are treated with approximately 1 molar equivalent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in the presence of a catalytic amount of acid and in an inert solvent, to give the corresponding l9-haloA -pregnadiene-3,20-dione derivatives (Vii). The latter A compounds may be converted into the corresponding A derivatives (Vlll) by further treatment with 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone under the conditions specified hereinbefore for the production of the d derivatives (VI).

The compounds of the present invention having a 160i, 17a-ketonide grouping, yield the corresponding 16u,17adiols, by conventional treatment with a strong acid such as formic acid. The obtained diols, upon conventional esterification in pyridine with an acylating agent, as for example acetic anhydride or caproic anhydride afiord the corresponding 16-acylates.

The latter 1602,170L-dil5 upon conventional condensation with a ketonide or aldehyde, such as benzaldehyde, acetophenone, methylethyl ketone, acetone, and the like, in the presence of an acid, yield the corresponding 16a, l7a-methylenedioxy derivatives, wherein the substituents in the methylenedioxy group may be different from those of the previously hydrolyzed ketonide grouping.

The compounds of the present invention having a hydroxyl group at C-17ix, may be acylated by conventional treatment with an acylating agent, such as an anhydride derived from a hydrocarbon carboxylic acid of the type described hereinbefore, in the presence of p-toluenesultonic acid, to produce the corresponding l7a-esters.

The following specific examples serve to illustrate the present invention, but are not intended to limit the scope thereof: I

PREPARATION 1 To a solution of g. of 19-fiuoro-A -pregnene-3fl,17adiol-20-one (obtained in accordance with my US. patent application Serial No. 194,717, filed May 14, 1962, now US. Patent No. 3,124,574) in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonie acid and cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis on the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced 19-fluoro-A pregnene-35,17a-diol-20-one diacetate.

A suspension of 1 g. of the latter diacetate in 60 cc. of methanol was treated with a solution of l g. of potassium carbonate in 6 cc. of water; the mixture was boiled under reflux for 1 hour and then cooled in ice and diluted with Water. The formed precipitate was collected and recrystallized from acetone-hexane to yield 19-liu0ro-A pregnene-Ilfl,17e-diol-20-one 17-acetate.

By the same procedure, the starting compounds under A (obtained in accordance with the aforesaid patent application) were converted into the products under B.

PREPARATION 2 genated overnight in the presence of 0.5 g. of a 5% palladium on charcoal catalyst at atmospheric pressure and room temperature. Removal of catalyst and solvent and crystallization of the residue from acetone furnished 16(1- methyl-allopregnane-17a,19-diol-3,20-dione l7-acctate.

A solution of 5 g. of the latter compound in 25 cc. of pyridine was cooled to 0 C. Under stirring there was added 1.3 g. of tosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with 100 cc. of chloroform, washed wtih dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again wtih water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus there was obtained 1613 methyl-allopregnane-fla, 19-diol-3,20-dione 17-acetate-19-tosylate.

One gram of the latter tosylate was dissolved in 30 cc. of toluene and thereto was added 1 g. of sodium hydride suspended in mineral oil. The resulting mixture was refluxed for 5 hours. Then, 5 cc. of t-butanol were cautiously added to decompose the excess of hydride, and the whole was washed with. water, dried and evaporated to dryness. Alumina chromatography of the residue, followed by recrystallization from acetone-hexane yielded 16fi-methyl-2,19-cyclo-allopregnan-l7e-ol-3,20-dione.

A solution of 1 g. of the latter 2,19-cyclo compound in 50 cc. of ethanol was treated with 50 cc. of 70% sulfuric acid and kept for 5 hours on the steam bath. It was then poured into water and extracted with methylene chloride. The extract was successively washed with water, sodium bicarbonate solution and water. Thereafter it was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on alumina, thus affording 1tip-methyl-IOa-allopregnane-l7a,l9-diol- 3,20-dione.

A solution of 2 mol equivalents of bromine in 15 cc. of glacial acetic acid was added dropwise to asolution of l g. of the latter dione, in 25 cc. of acetic acid containing a few drops of 4 N hydrogen bromide in acetic acid. After five hours at room temperature, the mixture was poured into ice water and the precipitated dibromo deriva tive was collected, washed well with water, and dried. The dried material was refluxed for 14 hours with 2 g. of sodium iodide in 40 cc. of ethyl methyl ketone and then kept at room temperature for an additional 12 hours. After dilution with water, the product was extracted with ether, washed with sodium thiosulfate solution and water, and the ether was removed under reduced pressure.

The crude residue was refluxed for 30 minutes with 10 cc. of 'y-collidine. The solution was cooled, the precipitate removed and the filtrate was diluted with ether, washed with dilute hydrochloric acid, sodium bicarbonate solution and water. The dried extract was evaporated and the residue was recrystallized from ether-hexane affording 16fl-methyl-A -lom-pregnene-l7a,19-diol-3,20-dione.

Example I A solution of 1 g. of 19-fluoro-A -pregnen-35-01-20- one (obtained in accordance with my US. patent application Serial No. 194,717, filed May 14, 1962, now US. Patent No. 3,124,574), in cc. of toluene and 20 cc. of cyclohexanone was dried by distilling off 10 cc. of the solvent. A solution of 1 g. of aluminum isopropoxide dissolved in 7 cc. of anhydrous toluene was then 19-fiuoro-A -pregnene-3fl,17a diol 20-one-17-acetate (obtained in accordance with Preparation 1) was treated in accordance with the same procedure thus affording l9-fluoro-A -pregnen-17a-ol-3,20-dione acetate.

A solution of 0.17 g. of potassium hydroxide in 0.2 cc. of. water and 2.5 cc. of methanol was added over 30 minutes to a b iiling solution of 1 g. of the latter 3,20- diketo acetate, in 30 cc. of methanol under an atmosphere of nitrogen. Boiling was continued for a further 2 hours and the solution was then cooled, neutralized with acetic acid and concentrated under reduced pressure. Addition of water, followed by crystallization of the precipitated solid from acetone-hexane, produced 19- fluoro-A-pregnen-17a-ol-3,20-dione (Cpd. No. 5).

19-fluoro-16u-methyl-A -pregnene-3B,17a diol-20-one 17-acetate and 19-fluoro-16fl-methyl-A -pregnene-3fl,17mdiol-20-one 17-acetate (obtained according to Preparation 1) were treated by the same procedures as the correspond ing 16-desmethyl compound, thus affording respectively 19-fluoro-16a-methyl-A pregnen 17a-ol-3,20 dione (Cpd. No. 6) and 19-fluoro-16fi-methyl-A -pregnen-17aol-3,20-dione (Cpd. No. 7).

'The 19-chlor'o compounds listed under C (obtained in accordance with the aforementioned patent application or with Preparation No. 1) were treated following the procedures described for the corresponding 19-fluoro compounds, thus affording the products under D.

A mixture of 5 g. of 19-fluoro-A -pregnene-3,20-dione (Cpd. No. l), 150 cc. of anhydrous benzene, 60 cc. of ethyleneglycol distilled over sodium hydroxide and 800 mg. of p-toluenesulfonic acid monohydrate was refluxed for 12 hours with the use of an adapter for the continuous removal of the water formed during the reaction. Aqueous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 3,ZO-bis-cycloethylenedioxy-19- fluoro-A -pregnene (Cpd. No.15).

The Compounds Nos. 2 to 14, inclusive, obtained according to Example I, were treated following the samev procedure, thus affording respectively-- Cpd. No.:

16. 3,20--bis-cycloethylenedioxy-19-fluoro-16amethyl-M-pregnene 17. 3,ZO-bis-cycloethylenedioxy-l9-fiuoro-16B- methyl-M-pregnene 18. 3,20-bis-cycloethylenedioxyl 9-fiuoro- 1 6a,

17a-isopropylidenedioxy-M-pregnene 19. 3,20-bis-cycloethylenedioxy-19-fluoro-A pregnen-l7a-ol 20. 3,20-bis-cycloethylenedioxy-19-fluoro-16amethyl-A -pregnene-17a-o1 21. 3,ZO-bis-cycloethylenedioxy-19-fluoro-16B- methy1-A -pregnen-17a-ol 22. 3,2O-bis-cycloethylenedioxy-19-chloro-A pregnene 23. 3,20-biscycloethylenedioxy 19-chloro-16aq methyl-n -pregnene 24. 3,ZO-bis-cycloethylenedioxy-19-chloro-l6flmethyl-A -pregnene 25. 3,20-bis-cycloethylenedioxy-19-chloro-16a,

17a-isopropylidenedioxy-A -pregnene 26. 3,20-bis-cycloethylenedioxy-19-chl0ro-A pregnen-17a-ol 27. 3,20-bis-cycloethylenedioxy-19-chloro-16amethy1-A -pregnen-17u-ol 28. 3,20-bis-cycloethylenedioxy-l9-chloro-16pmethyl-A -pregnen-17a-ol Example III A solution of 2.5 g. of 3,ZO-bis-cycloethylenedioxy-19- fluoro-A' -pregnene (Cpd. No. 15), in 100 cc. of chloroform was cooled to 0 C. and mixed with 1.1 molar equivalents of monoperphthalic acid in ether solution. The mixture was kept at room temperature for 20 hours, diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 3,20 biscycloethylenedioxy-5a,6aoxido-19-fiuoro-pregnane (Cpd. No. 29).

When applying the above procedure to the Compounds Nos. 16 to 28 inclusive, there were obtained respectively- Cpd. No.:

,30. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19- fluoro-16a-methyl-pregnane 31. 3,20-bis-cycloethylenedioxy-S u,6a-oxidol 9- fluoro-lp-methyl-pregnane 32. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19- fluoro-16a,17ot-isopropylidenedioxy-pregnane 33. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19- fluoro-pregnan-17a-0l 34. 3,20-bis-cycloethyenedioxy-Sa,6a-oxido-19- fluoro-16a-rnethyl-pregnan-17a-ol 35. 3,20-bis-cycloethylenedioxy-Sa,6a-oxido-19- fluoro-l6p-methyl-pregnan-l7a-ol 36. 3,20-bis-cycloethylenedioxy-Sa,6ot-oxido-19- chloro-pregnane 37. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19- chloro-l6a-methyl pregnane 38. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19- chloro- 1 Gfl-methyl-pregnane 39. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19- chloro-16a,17a-isopropylidenedioxy-pregnane 40. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-l9- chloro-pregnan-l7a-ol 41. 3,20-bis-cycloethylenedioxy-5ot,6a-oxido-l9- chloro-l6a-methyl-pregnan-17a-ol 42. 3,ZO-bis-cycloethylenedioxy-5a,6ot-oxido-19- chloro-1618-methyl-pregnan-l7a-ol Example IV and the stirred mixture heated under reflux for 30 minutes. The condenser was then replaced by a calcium chloride tube, the ether allowed to boil off and when the internal temperature reached 54 C., the condenser was readapted and the mixture refluxed for an additional 4 hours. 400 cc. of a saturated solution of ammonium chloride was added slowly to the cooled mixture which was then stirred for minutes before transfer to a separatory funnel. The tetrahydrofuran layer was separated, dried and evaporated to dryness, thus affording a solid residue.

A solution of the above residue in 70 cc. of methanol and 7 cc. of 8% aqueous sulfuric acid was refluxed for 40 minutes. It was then neutralized with saturated sodium carbonate solution, concentrated to ca. co. in vacuo and poured into water. The formed precipitate was filtered olf and washed thoroughly with water and air dried.

A solution of the dry precipitate in 100 cc. of methanol and 50 cc. of 1 N aqueous sodium hydroxide was allowed to stand at room temperature under a nitrogen atmosphere for 24 hours. The solution was then concentrated under reduced pressure and without heating to half its volume, ice water was added and the crystalline precipitate filtered, washed and dried. Recrystallization from aqueous acetone gave l9-lluoro-6u-methyl-M-pregnene-3,20-dione (Cpd. No. 43).

The Compounds Nos. to 42, inclusive, were treated by the above method, furnishing respectively- Cpd.No.:

44. 19-fluoro-6a,16u-dimethyl-A -pregnene- 3,20-dione 45. 19-fiuoro-6u,1618-dimethyl-A -pregnene- 3,20-dione 46. 19-fluoro-6a-methyl-l6a,17a-isopropylidenedioxy-A -pregnene-3,ZO-dione 47. l9-fluoro-6a-methyl-A -pregnen-17aol-3,20-dione 48. l9-fiuoro-6a,l6u-dimethyl-A -pregnen- 17a-ol-3,20-dione 50. 19-ch1oro-6ot-methyl-A -pregnene-3,2O-dione 5 l 19-Chl0lO-6oc, l6a-dimethyl-A -preguene- 3,20-dione 52. 19-chloro-6a,lfl-dimethyl-M-pregnene- 3,20-dione 53. 19chloro-6a-methyl-16e,l7a-isopropyli denedioxy-A -pregnene-3,ZO-dione 54. 19'chloro-6m-methyl-A -pregnen-17aol-3,20-dione 55. l9-chloro-6m,l6a-dimethyl-A -pregnenl7u-ol-3,20-dione 56. l9-chloro-6u,l6 8-dimethyl-A -pregnen- 17e-ol-3,20-dione Example V Into a suspension of 1 g. of 3,20-bis-cycloethylenedioxy-5u,6oz-oxide-l9-fiuoro-pregnane (Cpd. No. 29) in cc. of anhydrous ethyl acetate at 10 C. was passed a slow stream of dry hydrochloric acid, after 10 minutes all the solid material was dissolved. The gas was passed through the reaction mixture for a total of 5 hours. The solution was then washed abundantly with water, the organic layer wasseparated, dried over sodium sulfate and evaporated to dryness. The residue was washed with water to neutrality and dried. Recrystallization from methylene chloride afiorded Got-chloro-19-fiuoro-A -pregnene-3,20-dione (Cpd. No. 57).

By the same procedure, the Compounds Nos. 30 to 42, inclusive, were respectively converted into Cpd.No.:

58. 6a-chloro-19-fluoro-1Ga-methyl-M-pregnene- 3,20-dione 59. 6a-chloro-19-fiuoro-16B-methyl-A -pregnene- 3,20-dione 60. 6u-chloro-19-fiuoro-16a,l7a-isopropylidenedioxy-M-pregnene-S,ZO-dione 61. Ger-chloro-19-fluoro-A -pregnen-17usol- 3,20-dione 62. Got-chloro-19-fiuoro-lfie-methyl-d pregnen- 17ar-ol-3,20-dione 64. 6a,19-dichloro-A -pregnene-3,20-dione 65. 6a,l9-dichloro-l6a-methyl-A -pregnene- 3,2G-dione 66. 60:,19-dich1oro-l6fl-methyl-d pregnene 3,20-dione 68. 6e,l9-dichlororA -pre'gnen-1.7br-ol 3,20 dione 70. 6a, 1 9-dichlorol mi -methyl.-A -pregnen- 1701- ol-3,20-dione Example VI 2.8 cc. of boron trifiuoride etherate was slowly added with stirring to 220 mg. of anhydrous hydrogen fluoride cooled in an acetone-Dry Ice bath.

To a solution of 1 g. of 3,20-bis-cycloethylenedioxy- 5a,6a-oxido-19-fiuoro-pregnane (Cpd. No. 29) in. 10 cc. of a mixture of equal parts of benzene and ether was added 1.3 cc. of the fiuorohoric acid reagent; The mixture was kept for 3 hours at room temperature, then washed four times with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was mixed with 35 cc. of anhydrous ethyl acetate and there was passed a-slow'stream of dry hydrochloric acid. The gas was passed through the reaction mixture for a total of 5 hours. The solution was then washed .abundantly with water, the organic layer was separated, dried over sodiumrtsulfate and evapo rated to dryness. The residue was washed with water to neutrality and dried. Recrystallization from methylene chloride afforded 6a,19-difiuoro-A -pregnene-3,ZO-dione (Cpd. No. 71).

When applying the same procedure to the Compounds Nos. 30 to 42, inclusive, there were respectively obtained Cpd. No.1

72. 6a,19-difluoro-16a-methyl-A -pregnene-3,20-.

dione 73. 6a,l9-difiuoro-16B-methyl-A -pregnene-3,20

dione 74. 6a,l9-difiuoro-l6a,l7a-isopropylidenedioxy-M- pregnene-3,20-dione 75. 6a, 1 9-difluorp-A -pregnen-17e-ol-3,20-dione 76. 6a,l9-difiuoro-l6a-methyl-A -pregnen-1701-01- 3,20-dione 7 7. 6a, 1 9-difluoro- 16fi methyl-A pregnen-l701-01- 3,20-dione 78. a-fiuoro-l9-chloro-A -pregnene-3,20+dione 79. 6a-fiuoro-19-chloro-IGwmethyLM-pregnene-- 3,20-dione 80. 6tt-fiuoro-l9-chloro-I6B-methyLA -pregnene- 3,20-dione 81. 6a-fluoro-19-chloro-16a,l7a-isopropylidenedioxy-A -pregnene-3,ZO-dione 82. oer-fluoro-19-chloro-A -pregnen-17a-ol-3,20dione 83. 6m-fluoro-19-chloro-16a-methyl-A -pregnen-17aol-3,20-dione Example VII A mixture of 500 mg. of l9-fluoro-6e-methyl-A pregneue-3,20-dione (Cpd. No. 43), 10 cc. of dioxane and 350 mg. of 2,3-dichloro-5,6dicyano-1,4-henzoquinonewas refluxed for 10 hours. It was then cooled, the. 2,3-dichloro-5,6-dicyano-1,4-henzohydroquinone formed during the reaction filtered olf, and the filtrate evaporated to 11 dryness. The residue was dissolved in acetone and filtered through 10 g. of alumina. Crystallization from acetone-hexane gave l9-tluoro-6a-methyl-A -pregnadiene-3,20-dione (Cpd. No. 85).

The Compounds Nos. 1 to 14, inclusive, were treated following the same procedure, thus affording correspondingly- Cpd. No:

86. 19-fluoro-A -pregnadiene-3,ZO-dione 87. 19-fluoro-16a-methyl-A -pregnadiene-3,20-

dione 88. 19-fluoro-16fl-methyl-A -pregnadiene-3,20-

dione 89. 19-flu5ro-16a,17a-isopropylidenedioxy-A pregnadiene-3,20-dione V 90. 19-fluoro-A -pregnadien-17a-ol-3,20-dione 91. 19-fiuoro 16a-methyl-A -pregnadien-17a-o1 3,20-dione 3,20-dione 93. 19-ch1oro-A -pregnadiene-3,ZO-dione 94. 19-chloro-16a-methyl-A -pregnadiene-S,20

dione 95. l9-chloro-16p-methyl-A -pregnadiene-3,20-

dione 96. 19-chloro-l6a,17a-isopropylidenedioxy-A pregnadiene-3,20-dione 97. 19-chloro-A -pregnadien-17a-ol-3,20-dione v 98. 19-chloro-16a-methyl-A -pregnadien-17ot-o1- 3,20-dione 99. l9-chloro-16,3-methyl-A -pregnadien-17a-0l 3,20-dione 1 Example VIII When applying the proceduredescribed in the foregoing example toCompounds Nos. 44 to 84, inclusive, there were obtained the corresponding A -derivatives.

Example IX A suspension of 1 g. of 19-fluorqr6a-methyl-A -pregnene-3,20-dione (Cpd. No. 43), -in 715cc. of anhydrous peroxide free dioxane was treated with 1.2 cc. of freshly distilled ethyl orthoformate and 0.8 g. of p-toluene sulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 0.8- cc. of pyridine was added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetonehexane afforded 19-fluoro-6-methyl-3-ethoxy- A -pregnadien-20-one.

A solution of 1 g. of the latter compound in 20 cc. of tetrahydrofuran was cooled to C. and there were added 1.05 molar equivalents of 2,3-dichloro-5,6-dicyano 1,4- benzoquinone and 100 mg. of p-tbluenesulfonic acid. The resulting mixture was further stirred at 0 C. for 30 minutes. The precipitated hydroquinone was filtered off and 100 cc. of methylene dichloride were added to the filtrate. The organic solution was washed with aqueous sodium hydroxide solution until the washings were colorless, then with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 19-fluoro-6- methyl-A -pregnadiene,20-dione (Cpd. No. 100').

The Compounds Nos. 1 to 14, inclusive, were treated following the same procedure, thus affording corresponds y.

Cpd.No.:

1.01. 19-fluoro-A --pregnadiene-3,20-dione 102. 19-fluoro-l6a-methyl-A -pregnadiene-3,20-

dione r 103. 19-fluoro-16p-methyl-A -pregnadiene-3,20-

dione y 104. l9-fluor'o-16a,17a-isopropylidenedioxy-A#- preghadiene-LZO-dione 105. l9-tluoro-A-pregnadien-l7u-0l-3,20-dione 106. l9-fluoro-16amethyl-A '-pregnadien-17a-ol- 3,20-di0ne 107. =l9-fiuoro-1GB-methyl-A --pregnadien-17a-ol- 3,20-dione 108. 19-chloro-A --pregnadiene-3,20-dione 109. 19-chloro-16a-methyl-A --pregnadiene-3,20-

dione 110. 19-ch1oro-16fl-methyl-A --pregnadiene-3,20-

dione 1 11. 19-chloro-16a,17a,isopropylidenedioxy-M- pregnadiene-3,20-dione 112. 19-chloro-A --pregnadien-1711-01-3,20-dione 1 1 3 19-chloro-16a-methyl-M -pregnadien-17a-ol 3,20-dione 114. l9-chloro-16fl-methyl-A -pregnadien-l7a-ol- 3,20-dione Example X When applying the procedure described in the foregoing example to Compounds Nos. 44 to 84, inclusive, there were obtained the corresponding A --derivatives.

Example XI 19-fluoro-6-methyl-A -pregnadiene-3,20-dione (Cpd. No. was treated in accordance with Example VII, thus affording 19-fiuoro-6methyl-A '-pregnatriene-3,20- dione (Cpd.No.115).

Upon treatment by the same procedure of compounds Nos. 101 to 114 inclusive, there were respectively produced- Example XII When applying the procedure described in Example VII to the M' -compounds obtained in accordance with Example X, there were obtained the corresponding A derivatives.

Example XIII To a solution of 5 g. of l9-fluoro-A -pregnen-17a-ol- 3,20-dione (Cpd. No. 5) in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to elfect hydrolysis of the excess anhydride. '1' he benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced l9-fluoro-A -preguen- 17a-ol-3,20-di0ne acetate (Cpd. No.

13 a The Compounds Nos. 6, 7, 12, 13 and 14 were treated following the same procedure, thus affording respectively- Cpd. No.: I

' 131. 19 fluoro 16o: methyl A pregnen-17a o1 3,20-dione acetate 132. 19-fluoro-16fi-methyl-A -preguen-l7e 1 ol 3,20-

dione acetate 133. 19 chloro A pregnen 17oz o1 3,20 dione acetate 134. 19-chloro-16a-methyl-A -pregnen 17a. ol-3,20

dione acetate 135. 19-ch1oro-165 methyl A pregnen 17a ol- 3,20-dione acetate Example XIV The Compounds Nos. 47, 4s, 49, 54, 55 and 56 were treated in accordance with Example XIII, thus giving respectively- Example XV The Compounds Nos. 61, 62, 63, 68, 69 and 70 were treated in accordance with Example XIII, thus giving respectively- Cpd. No: i

142. 6a chloro 19 fluoro A pregnen 17o: ol-

3,20-dione acetate 143. 6 z-Ch101'0-19-fit1010-16m methyl A pregnen- 17a-ol-3,2D-dione acetate 144. 6a chloro 19 fluoro 1613 methyl A pregnen-17a-o1-3,20-dione acetate 145. 611,19 dichloro A pregnen 17oz ol 3,20-

dione acetate 146. 60;,19 dichloro 16o: methyl A pregnen- 17a-ol-3,20-dione acetate 147. 6oz,19-dichloro-16B methyl A pregnen 17aol-3,20-dione acetate Example XVI The Compounds Nos. 75, 76, 77, 82, 83 and 84 were treated in accordance with Example XIII, thus afiording respectively--- 1 Example XVII The Compounds Nos. 90, 91, 92, 97, 98, 99, 105, 106,

1107, 112, 113, 114, 120, 121, 122, 127, 128 and 129, were treated in accordance with Example XIII, thus affording the corresponding acetates.

14 Example X VIII.

The starting compounds of Examplesv XIII, XIV; XV,

XVI and XVII were treated in accordance: with Example XIII, except that acetic. anhydride was substituted by caproic anhydride, thus yielding the corresponding; caproates.

Example Xl-X 1 g. of 19-fluoro-16a,17a-isopropylidenedioxy-M-pregnene-3,2.0-dione (Cpd. No. 4) was heated onthe. steam bath with 20 cc. of 60% formic acid for 1 hour, cooled, diluted with water and the precipitate. was; collected,

' washed with water, dried and recrystallized. from; acetone.-

hexane, thus atfording 19fluoro-Af*-pregnene-16e,f'lardioh 3,20-dione (Cpd. No- 154 By the same procedure, the compounds Nos. 11, 4.6, 53, 60, 67, 74, 81, 89, 96, 1'04, 111', 119, 1.26 were trans-- formed respectively into- Cpd. No.:

155. 19-chloro-M-pregnene16a,17-diol-3,20rdione 156. 19-fluoro-6avmethylrA -pregnene 16u-,.1.7'u.-di'o1- Example XX A mixture of 1g. of 19-fluoro-A -pregnene-16a,17adio1-3,20-dione (Cpd. No. 154), 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with Water and dried. Crystallization from acetone-hexane gave the 16-acetate of 19-fluoro-A pregnene-l6a,17a-diol-3,20-dione (Cpd. No. 168).

The Compounds Nos. 155 to 167, inclusive, were treated by the same procedure thus yielding respectively-- Cpd. No.:

169. 19-chloro A -pregnene-16u,17m-diol-3,20-dione 16-acetate 170. 19-fluoro 6a-methyl-M-pregnene-16a,l7a-dio1- 3,20-dione IG-acetate 171. 19-chloro-6m-methyl-A pregnene-16a,17a-dio1- 3,20-dione 16-acetate 172. Got-chloro-19-fluoro-A -pregnene-16a,17rx-dio1- 3,20-dione lfi-acetate 173. 6a,19-dichloro-A -pregnene-16a,17u-di0l-3,20-

dione 16-acetate 174. 6a,19-difluoro-A -pregnene-16a,17a-dio1-3,20-

dione 16-acetate 175. fia-fiuoro-l9-chloro-A -pregnene-16a,17a-dio1- 3,20-dione lfi-acetate 176. 19-fiuororA -pregnadiene-l6a,17u-diol-3,20-

dione 16-acetate 177. 19-ch1oro-A -pregnadiene-16u,17a-dio1-3,20-

dione 16-acetate 178. 19-fluoro-A -pregnadiene-16a-17a-diol-3,20-

dione .16-acetate 179. 1'9-ch1oro-A -pregnadiene-16a-17a-diol-3,20-

dione Iii-acetate 180. 19-fluoro-A --pregnatriene-16a,17e-diol-3,20-

dione 16-acetate 181. 19-chloro-A -pregnatriene-16a, 17a-diO1-3,20

dione 16-acetate Example XXI The Compounds Nos. 169 to 181, inclusive, were treated in accordance with Example XIII, thus affording the corresponding 17-acetates.

Example XXII 19 fluoro-N-pregnene 16a,17a-dlOl-3,20-dl0fl6 (Cpd. No. 154) was treated following the procedure described in Example XIII, thus yielding,19-fluoro-A -pregnene- 16a,17a-diOl-3,20-di0n diacetate (Cpd. No. 182).

Example XXIII A suspension of 5 g. of 19-fiuoro-A -pregnene-3,20- dionc (Cpd. No. l) in 37.5 cc. of anhydrous peroxidefree dioxane was treated with 6.0 cc. of freshly distilled ethyl orthoformate and 4.0 g. of p-toluenesulfonic acid.

The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 3.8 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetone- 'hexane afforded 19-fluoro-3-ethoxy-A -pregnadien-20- one.

A mixture of 5 g. of the latter 3-ethoxy compound, 2 g. of anhydrous sodium acetate and 100 cc. of acetone was treated with 32 cc. of water and the solution was cooled to a temperature between 0 and 5 C. There was then added 1.1 molar equivalents of N-chloro-succinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C. for 30 minutes. It was then diluted with water, kept overnight at 0 C. and the precipitate formed was collected, washed with water, dried under vacuum and recrystallized from acetone thus giving 65- chloro-19-fiuoro-A -pregnene-3,20-dione (Cpd. No. 183).

The Compounds Nos. 2 to 14, inclusive, were treated following the same procedure, thus affording respectively Example XXIV A suspension of 1 g. of 19-fluoro-A -pregnene-3,20-dione (Cpd. No. 1) in 7.5 cc. of anhydrous peroxide-free dioxane'was treated with 1.2 cc. of freshly distilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 0.8 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetonehexane afforded 19-fluoro-3-ethoxy-A -pregnadiene-20- one.

1 g. of the latter steroid was dissolved in 25 cc. of dimethylformamide. The solution was cooled to 0 C. and a stream of perchloryl fluoride was passed for 3 minutes; the solution was allowed to come slowly to 20 C.; it was then poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, then with water to neutrality, dried over anhydrous sodium sulfate, and evaporated to dryness. By chromatography over washed alumina there was produced 6,3,l9-difluoro-A -pregnene-3,20-dione (Cpd. N0. 197).

'When applying the above procedures to Compounds,

Nos. 2 to 14 inclusive, there were respectively produced- Cpd. No.:

198. 618,19 difluoro-16oc-methyl-A -pregnene-3,20-

dione 199. 65,19 difluoro-l6p-methyl-A -pregnene-3,20-

dione 200. 65,19 difluoro-16a,17a-isopropylidenedioxy-A pregnene-3,20-dione 201. 6,9,19-difluoro-A -pregnen-17a-ol-3,20-dione 202. 6 3,19 difluoro l6a-methyl-A -pregnen-1741-01- 3,20-dione v 203. 618,19 difluoro-l6fi-methyl-A -pregnen-17a-ol- 3,20-dione 204. 6fi-fluoro-19-chloro-A -pregnene-3,20-dione 205. 6B fluoro-19-chloro-16a methyl-M-pregnene- 3,20-dione 1 206. 6 3 -fluoro 19 chloro-16fl-methyl-A -pregnene- 3,20-dione 207. 618 fluoro-19-chloro-16a,17a-isopropy1idenedioxy-M-pregnene-S,ZO-dione 208. 6fi-fluoro 19 chloro-M-pregnen-17a-ol-3,20-

dione 209. 6,8 fluoro-19-chloro-l6u-methyl-A -pregnen- 17a-ol-3,20-dione 210. 6 3 fluoro-19-chloro-16p-methyl-A -pregneu- 17a-ol-3,20-dione Example XXV To a solution of 20 cc. of 4 N methylmagnesium bromide in ether was added, with stirring, a solution of 2 g. of 3,20 bis cycloethylenedioxy 50:,601. oxido-19-fluoropregnane (Cpd. No. 29) in 60 cc. of dry tetrahydrofuran and the stirred mixture heated under reflux for 30 minutes. The condenser was then replaced by a calcium chloride tube, the ether allowed to boil off and when the internal temperature reached 54 C., the condenser was readapted and the mixture refluxed for an additional 4 hours. 400 cc. of a saturated solution of ammonium chloride was added slowly to the cooled mixture which was then stirred for 15 minutes before transfer to a separatory funnel. The tetrahydrofuran layer was separated, dried and evaporated to dryness.

A solution of the above residue in 70 cc. of methanol and 7 cc. of 8% aqueous sulfuric acid was refluxed for 40 minutes. It was then neutralized with saturated sodium carbonate solution, concentrated to ca. 20 cc. in vacuo and poured into water. The formed precipitate was filtered off and washed thoroughly with water and air dried.

A solution of the dry precipitate, 7 cc. of dry pyridine was cooled to -10 C., treated with 0.4 cc. of thionyl chloride and the mixture allowed to stand for 4 minutes at this temperature. Ice-water was added and the crystalline precipitate was filtered, washed and dried, yielding 222. 19 chloro fifl-methyl-M-pregnen-17a-ol-3,20-

, dione 223. 19 chloro-65,16a-dimethyl-A -pregnen-17a-ol- 3,20-dione 224. 19 chloro 65,16,8-dimethyl-A -pregnen-17u-ol 3,20-diono Example XX VI The Compounds Nos. 183 to 224, inclusive, were treated following the procedure described in Example V11, thus affording the respective A -derivatives.

Example XXVI] A solution of 5 g. of A -u-pregnen-19-ol-3,20-di0ne (Cross US. patent application Ser. No. 231,831, filed October 19, 19 62), in 25 cc. of pyridine was cooled to 0 C.

Under stirring there was added 1.1 molar equivalents of tosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with 100 cc. of chloroform, washed with dilute hydrochloride acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus there was obtained the crude 19-tosylate of the starting compound.

A mixture of 4 g. of the crude tosylate, 4 g. of dry lithium fluoride and 50 cc. of dimethyl formamide was refluxed for 1 hour. The mixture was then poured into water, the formed precipitate filtered off and crystallized from acetone-hezane to give Compound No. 225, namely 19-fluoro-A -l0a-pregnene-3,20-dione.

When applying the above procedure to the starting compounds listed under A (obtained in accordance with the aforesaid patent application), there were obtained the correspondirig products under B.

The starting compounds indicated hereinbefore were treated following the above procedures, except that lithium 18 fluoride was substituted by lithium chloride, thus yielding respectively- Cpd. No:

232. 19-chloroA -10a-pregnen-3,20-dione 233. 19 chloro 16oz methyl-A -10a-pregnene-3,20-

dione v 234. 19 chloro 16B methyl-A -10a-pregnene-3,20-

dione 235. 19 chloro 161;,17 a isopropylidenedioxy A 10a-pregnene-3,20-dione 236. 19-chloro-A -1Oa-pregnen-l7a-ol-3,20-dione 237. 19 chloro-16a methy1-A -10a-pregnen-17a-ol- 3,20-dione 238. 19 chloro 1SB-methyLM-lOa-pregnen-fla-ol- 3,20-dione Example XX VIII A mixture of 5 g. of 19 fiuoro-A -10apregnene-3,20- dione (Cpd. No. 225) 150 cc. of. anhydrous benzene, 60 cc. of ethyleneglycol distilled over sodium hydroxide and 800 mg. of p-toluene sult'onic acid monohydrate was refluxed for 12 hours with the use of an adapter for the continuous removal of the water formed during the reaction.

Aqueous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 3,ZO-biscycloethyleriedioxy-l9- fiuoro-M-lOa-pregnene (Cpd. No. 239).

T-he Compounds, Nos. 226 to 238,- inclusiv'e, obtained according to Example XXVII, were treated following the same procedure, thus affording respectively-- Cpd. No.:

240. 3,ZO-bis-cycloethylenedioxy-19-fluoro-16mmethyI-A -IOa-pregnene,

241. 3,20-bis-cyc1oethy1enedioxy-19-iluoro-16B- methyI-AMOaregnene 242. 3,ZO-bis-cycloethylenedioxy-19-fluoro-16u,17a-

isopropylidenedioxy-A -l0a-pregnene 243 -3,20-bis-cycloethylenedioxy 19fluoro-A -10apregnen-17m-ol 244. 3,20-bis-cycloethylenedioxy-l9-fluoro-16mmethyl-A l0e-pregnen-l7a-ol 246. 3,ZO-bis-cycloethylenedioxy-l9-chloro-A -10w pregnene 247. l3,20-bis-cycloethylenedioxy-19-chloro-16a- E methy1-A -1Ou-pregnene 24-8. 3,20-bis-cycloethylenedioxy-19-chloro-16pmethyl-Mdtla-pregnene 249. 3,lO-bis-cycloethylenedioxyd9-chloro-16a,

1-7u-isopropylidenedioxy-A l0a-pregnene 250. 3,-2O-bis-cycloethylenedioxy-19-chloro-A -10apregnen-lh-ol 251. -3,20-bis-cycloethylenedioxy-l9-chlorol6amethyl-M-lOa-pregnen-l7a-ol -2. l3, 20-bis-cycloethylenedioxy-19-chloro-16pmethyl-A IOa-pregnen-flwol Example XXIX Nos. 240 to 252, inclusive, there were obtained respectively- 1 9 Cpd. No.:

- 254. 3,20-bis-cycloethylenedioxy-5a,6a-oxidol 9- :fluoro- 16a-methyl- IOa-pregnane 25 5 3,20-bis-cycloethylenedioxy-5a,6a-oxidol 9- fluoro-16fl-methyl- 1 Oa-pregnane 25 6. 3 ,20-bis-cycloethylenedioxy-Sa,6a-oxido-19- fluoro-16a,17a-isopropylidenedioxy-10a-pregnane 257. 3,ZO-bis-cycloethylenedioxy-5a,6u-oxido-19- fiuoroi Oa-pregnan-I 7a0l 258. 3,20 bis-cycloethylenedioxy-5a,6a-oxido- 1 9- fluoro-16u-methyl-10a-pregnan-17a-ol 259. 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19- fluoro-l Gfl-methyl-l Oa-pregnamll 712-01 260. 3,20-bis-cycloethylenedioxy-Sa,6a-oxido-19- chIOro-IOaregnane a261. -3,20-bis-cycloethylenedioxy-Sw6a-oxidol9 chloro-IGa-methyI-IOu-pregnane 262. 3,-20-bis-cycloethylenedioxy-5a,6a-oxido-19- chloro-l 6fl-methyl- IOa-pregnane 263 3,20-bis-cycloethylenedioxy-5a,'6a-oxido-l 9- chloro-16w17a-isopropylidenedioxy-IOa-pregnane 264. 3,20-bis-cycloethylenedioxy-5a,6a-oxido- 1 9- chlro-10a-pregnan-17a-ol 265 3,20-bis-cycloethylenedioxy-a,6a-oxido- 1 9- chloro-16u-methyl-1Oar-pregnan-1701-01 266. -3,20-bis-cycloethylenedioxy-5a,6a-oxidol 9- chloro-l613-methyl-a-pregnan-17u-ol Example XXX of 3,20 bis cycloethylenedioxy-5a,6a-oxido-19-fiuoro- IOa-pregnane (Cpd. No. 253) in 60 cc. of dry tetrahydrofuran and the stirred mixture heated under reflux for 30 minutes. The condenser was then replaced by a calcium chloride tube, the ether allowed to boil off and when the internal temperature reached 54 C., the condenser was readapted and the mixture refluxed for an additional 4 hours. 400 cc. ofa saturated solution of ammonium chloride was added slowly to the cooledmixture which was then stirred for minutes before transfer to a separatory funnel. The tetrahydrofuran layer was separated, dried and evaporated to dryness, thus affording a solid residue.

A solution of the above residue in 70 cc. of methanol and 7 cc. of 8% aqueous sulfuric acid was refluxed for 40 minutes. It was then neutralized with saturated sodium carbonate solution, concentrated to ca. cc. in vacuo and poured into water. The formed precipitate was filtered off and washed thoroughly with water and air dried.

A solution of the dry precipitate in 100 cc. of methanol and 50 cc. of 1 N aqueous sodium hydroxide was allowed to stand at room temperature under a nitrogen atmosphere for 24 hours. The solution was then concentrated under reduced pressure and without heating to half its volume, ice water was added and the crystalline precipitate filtered, washed and dried. Recrystallization from aqueous acetone gave l9-fluoro-6a-methyl-A -10apregnene-3,20-dione (Cpd. No. 267).

The Compounds, Nos. 254 to 266 inclusive, were treated by the above method, furnishing respectively Cpd. No.:

268. 19 fluoro 6a,16a-dimethyl-A -1Oaregnene- 3,20-dione 269. l9-fluoro-6a-16fi-dimethyl-A -l0apregnene-3 -20-dione 270. 19-fiuoro-6a-methyl-16a,l7a-isopropylidenedioxy-A -10e-pregnene-3,20-dione V 271 19-fiuoro-6a-methyl-A -1Oaregnen- 17a-ol-3,20 dione 272. l9-fluoro-6a,16a-dimethyl-A -IOa-pregnem- 17a-ol-3,20-dione Example XXX! Into a suspension of 1 g. of 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19-fluoro-10a-pregnane (CpdpNo. 253) in 35 cc. of anhydrous ethyl acetate at 10 C. was passed a slow stream of dry hydrochloric acid, after 10 minutes all the solid material was dissolved. The gas was passed through the reaction mixture for a total of 5 hours. The solution was then washed abundantly with water, the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue was washed with water to neutrality and dried. Recrystallization from methylene chloride afforded 6u-chloro-19-fluoro-A -10a pregnene-3,20-dione (Cpd. No.281).

By the same procedure, the Compounds Nos. 30 to 42 inclusive, were respectively converted into- Cpd No.

282. Got-chloro-19-fluoro-16m-methyl-A -10apregnene-3,20-dione 283. 6a-Chl0l0- 1,9-fluoro- 1 6B-methyl-M- 10apregnene-3,20-dione 284; Got-chloro-19 fluoro-16a,17e-isopropylidenedioxy-A' -10a-pregnene-3,20-dione 285. oa-chloro- 19-fluoro-A -1 Oa-pregnen- 17a-ol-3,20-dione 286. 6a-chloro-l9-fiuoro-16a-methyl A -l0apregnen-17u-ol-3 ,20-dione 287. 6a-chloro-l9-fluoro-16 3-methyl-A -10a pregnen-17a'-ol-3,20-dione 28 8. 6a,19-dich1oro-A -l0a-pregnene-3 ,ZO-dione 289. 6a, 19-dichlorol 6a-methyl- A -l 0apregnene-3,20-dione 290. 6a,19-dichloro-16B-methyl-A -l0ocpregnene-3,20-dione 291. 6a,19-dichloro-16a,17a-isopropylidenedioxy- A -10a-pregnene-3 ,20-dione 292. 6a,19-dichloro-A -10a-pregnen-17aol-3,20-dione 293 601,19-diChlOIO-l 6a-methyl-A -10otpregnen- 17a-Ol-3,20-dl01l6 294. 6a,l9-dichloro-16 3-methyl-A -IOa-pregnen- 17a-ol3,20-dione Example XXX II 2.8 cc. of boron trifluoride etherate was slowly added with stirring to 220 mg. of anhydrous hydrogen fluoride cooled in an acetone-Dry Ice bath.

To a solution of 1g. of 3,20-bis-cycloethylenedioxy- 5a,6a-oxido-l9-fluoro-l0a-pregnane (Cpd. No. 253) in 10 cc. of a mixture of equal parts of benzene and ether was added 1.3 cc. of the fiuoroboric acid reagent. The mixture was kept for 3 hours at room temperature, then washed four times with water, 'dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was mixed with 35 cc. of anhydrous ethyl acetatev and there was passed a slow stream of dry hydrochloric acid. The gas was passed through the reaction mixture for a total of 5 hours. The

solution was then washed abundantly with water, the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue was washed with water to neutrality and dried. Recrystallization from methylene chloride afforded 6u,19-difluoro-A -10a-pregnene-3,20-dione (Cpd. No. 295).

When applying the same procedure to the Compounds Nos. 30 to 42 inclusive, there were respectively obtained- Example XXXIII A mixture of 500 mg. of 19-fluoro-6m-methyl-A -10a pregnene-3,20-dione (Cpd. No. 267 10 cc. of dioxane and 350 mg. of 2,3-dichloro-5,6-dicyano-1,4-benzoqui-' none was refluxed for 10 hours. It was then cooled, the 2,3-dichloro-5,6-dicyano-l,4 benzohydroquinone formed during the reaction filtered off, and the filtrate evaporated to dryness. filtered through 10 g. of alumina. Crystallization from acetone-hexane gave 19-fluoro-6a-methyl-A -IOa-pregnadiene-3,2( i-dione (Cpd. N0. 303).

The Compounds Nos 225 to 238 inclusive, were treated following the same procedure, thus affording correspondingly- Cpd. No.:

310. 19-fluoro-A -1Oeregnadiene-BJO-dione 3 11. 19-fluoro-16u-methyl-A -10m-pregnadiene- 3,20-dine 312. 19-fiuoro-16fl-methy1-A -1Oa-pregnadiene- 3,20-dione 314. 19-fiuoro-A *-IOaregnadien-17e-ol-3,20-

dione 315. 19-fiuoro-16a-methyl-A -u-pregnadien- 17a-ol-3,20-dione 317. 19-chloro-A fi-10a-pregnadiene-3,ZO-dione 318. 19-chloro-l6a-methyl-Afi-lOu-pregnadiene- 3,20-di0ne 319. 19-chloro-1fie-methyl-Nfi-IOQt-pregnadiene- 3,20-dioue 320. 19-chloro-16m,17ot-isopropylidenedioxy-A 10aregnadiene-B,20-dione 321. 19-chloro-A -1Oaregnadien-17oz-ol-3,20-

dione The residue was dissolved in acetone and 322 l9-chloro-16a-methyl-A -IOu-pregnadien- 17a-ol-3,20-dione 323. 19-chloro-IGfl-methyl-AH 10a-pregnadien 17a-ol-3,20-dione Example XXX! V When applying the procedure described in the foregoing example to Compounds Nos. 268 to 308, inclusive, there were obtained the corresponding A -derivatives.

Example XXX V A suspension of 1 g. of 19-fluoro-6a-methyl-A"-10epregnene-3,20-dione (Cpd. No. 267), in 7.5 cc. of anhydrous peroxide free dioxane was treated with 1.2 cc. of freshly distilled ethyl orthoformate and 0.8 g. of ptoluenesulfonie acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 0.8 cc. of pyridine were added and thenwater. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetone-hexane atforded 19-fluoro- 6-rnethyl-3-ethoxy-A -10a-pregnadien-20-one.

A solution of 1 g. of the latter compound in 20 cc. of tetrahydrofuran was cooled to 0' C. and there were added 1.05 molar equivalents of 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone and mg. of p-toluenesulfonic acid. The resulting mixture was further stirred at 0 C. for 30 minutes. The precipitated hydroquinone was filtered off and 100 cc. of methylene dichloride were added to the filtrate. The organic solution was washed with 5% aqueous sodium hydroxide solution until the washings were colorless, then with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave l9-fluoro-6- methyl-A 40e-pregnadiene-3,20-dione (Cpd. No. 324).

The Compounds Nos. 225 to 238, inclusive, were treated following the same procedure, thus afiording correspondingly Cpd.No.:

325. 19-fluoro-A -10a-pregnadiene-3,20-dione 326. 19-fiuoro-16u-methyl-A -10a-pregnadiene-3,20-

dione 327. 19-flu0r0-l6,9-methyl-A -10a-pregnadiene-3,20-

dione 328. 19-fluoro-16a,17a-isopropylidenedioxy-M -10apregnadiene-3,20-dione 330. 19 fluoro-16a-methyl-A -IOarpregnadien-Haol-3,20-dione 331. 19 fluoro-16fi-methyl-A -10a-pregnadien-l7aol-3,20-dione 332. l9-chloro-A -10a-pregnadiene-3,20-dione 333. 19-chloro-l6a-methyl-A -10a-pregnadiene-3,20-

dione 334. 19-chloro-IGB-methyl-M -10m-pregnadiene-3,20-

dione 335. 19-chloro-16a,17a-isopropylidenedioxy-A' -10apregnadiene-3,20-dione 336. 19-chloro-A -IOa-pregnadien-17u-ol-3,20-dione 337. 19 -chloro-16e-methyl-A -ltla-pregadien-lhol-3,20-dione 3 3 8. 19-chloro-16fl-methyl-A -1Oa-pregnadien-17eol-3,20-dione Example XXXVI When applying the procedure described in the foregoing example to Compounds Nos. 268 to 308, inclusive, there were obtained the corresponding M' -derivatives.

Example XXX VII 19 fiuoro 6 methyl A 10cc pregnadiene 3,20- dione (Cpd. No. 324) was treated in accordance with Example VII, thus affording l9-tluoro-6-methyl-A 10apregnatriene-3,20-dione (Cpd. No. 339).

Upon treatment by the same procedure of Compounds 23 Nos. 325 to 338, inclusive, there were respectively produced Cpd. No.:

340. 19-fir1oro-A -10a-pregnatriene-3,ZO-dione 341. 19 fluoro 16a methyl #1 10a-pregnatriene-3,20-dione 342. 19 fiuoro 16a methyl A1416 IOa-pregnatriene-3,20-dione .343. 19 fiuoro. 16a,17a isopropylidenedioxy- A -10a-pregnatriene-3,20-dione 344. 19 fluoro-A IOa-pregnatriene-17a-ol-3,20-

dione 345. 19 fluoro 16a methyl A 10a pregnatrien-17a-ol-3,20-dione 346.- 19 fiuoro 16,3 methyl A 10a pregnatrien-17a-o1-3,20-dione 347. 19-chloro-A -10a-pregnatriene-3,20-dione 348. 19 --chloro-16a-methyl-A -10a-pregnatriene- 3,20-dione 349. 19 chloro-16fl-methy1-A -IOaregnatriene- 3,20-dione 350. 19 chloro-16a,17a-isopropylidenedioxy-A 10a-pregnatriene-3,20-dione 351. 19 chloro A -1Oa-pregnatrien-17m-ol-3,20-

dione 352. 19 chloro 16a-methyl-A 4' -1Oa-pregnatrien- 17a-Ol-3,20d101l6 353. 19 chloro 16p-methyl-A -1Oa-pregnatrien 17a-ol-3,20-dione Example XXX VIII When applying the procedure described in Example XXXIII to the M -compounds obtained-in accordance with Example XXXVI, there were obtained the corresponding A -derivatives.

Example XXXIX effect hydrolysis of the excess anhydride. The benzene layer was separated and washed with sodium carbonate solution and water. crystallization of the residue from ether-hexane produced Drying, evaporation and 1 19-fluoro-A -10a-pregnen-17u-ol-3,2O-dione acetate (Cpd.

The Compounds Nos. 230, 231, 236, 237 and 238 were -treated following the same procedure, thus atfording respectively- Example XL The compounds Nos. 271, 272, 273, 278, 279, and 280 were treated in accordance with Example XXXIX, thus giving respectively- Cpd. No.:

360. 19-fiuoro-6a-methyl-A -IOa-pregnen-17a-ol- 3,20-dione acetate 361. l9-fluoro-6a,16a-dimethyl-A -IOa-pregnen- 17a-ol-3,20-dione acetate 362. 19-fluoro-6a,16fi-dimethyl-A -IOa-pregnen-l7aol-3,20-dione acetate 363. 19-chloro-6a-methyl-A -l0a-pregnen17a-o1- 3,20-dione acetate 364. 19-chloro-6a,16m-dimethyl-A -1ou-pregnen- 17a-0l-3,20-dione acetate 3 65. 19-chloro-6a,16p-dimethyl-A -1Oa-pregnen- 17a-ol-3,20-dione acetate Example XLI The compounds Nos. 285, 286, 287, 292, 293, and 294 were treated in accordance with Example XXXIX, thus giving respectively Cpd. No.:

366. 6a-chloro-19-fluoro-A -10a-prcgnen-17a-ol- 3,20-di0ne acetate 367. Gut-chloro-19-fluoro-16a-methyl-A -10a-pregnen-17a-ol-3,20-dione acetate 3 68. 6a-chloro-19-fiuoro-16B-methyl-A -IOu-pregnen-17a-ol-3 ,20-dione acetate 369. 6a,19-dichloro-A -1Oa-preguen-l7a-0l- 3,20-

dione acetate 370. 6a,19-dichloro-16a-methyl A -lOa-pregnen- 17a-o1-3,20-dione acetate 371. 6a,19-dichloro-16a-methy1-A -1Oa-pregnen- 17a-ol-3,20-dione acetate Example X LII The Compounds Nos. 299, 300, 301, 306, 307, and 308 were treated in accordance with Example XXXIX, thus affording respectively Cpd. No.:

372. 6oz,19-difiuoro-A -10a-pregnen-17a-0l-3,20-

dione acetate 373. 6a,19-difiuor0-16a-methyl-A -IOu-pregnen- 17a-ol-3,20-dione acetate 3 74. 6e-19-difluoro-16 8-methyl-A -1Oa-pregnen- 17a-ol-3,20-dione acetate 375. 6a-fluoro-19-chloro-A -10u-pregnen-17a-o1- 3,20-dione acetate Example XLIII The Compounds Nos. 314, 315, 316, 321, 322, 323, 329, 330, 331, 336, 337, 338, 344, 345, 346, 351, 352, and 353 were treated in accordance with Example XXXIX, thus affording the corresponding acetates.

Example XLI V The starting compounds of Examples XXXIX, XL, XLI, XLII and XLIII were treated in accordance with Example XXXIX, except that acetic anhydride was substituted by caproic anhydride, thus yielding the corresponding caproates.

Example XLV 1 g. of 19-fluoro-l6u,17m-isopropylidenedioxy-A' 10apregnene-3,20-dione (Cpd. No. 228) was heated on the steam bath with 20 cc. of 60% formic acid for 1 hour, cooled, diluted with water and the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus affording 19-fluoro-A -IOa-pregnene- 16a,17a-diol-3,20-dione (Cpd. No. 378).

By the same procedure, the Compounds Nos. 235, 270, 277, 284, 291, 298, 305, 313, 320, 328, 335, 343 and 350 were transformed respectively into Cpd. No.:

379. 19-chloro-A 10oc-pregnene-l6u,l7a-diol-3 ,20-

dione 3 80. 19-fluoro-6a-methyl-A -10x-pregnene-16a,17a-

diol-3,20-dione 381. 19-chloro-6a-methyl-A -1Oa-pregnene-1611,1711- diol-3,20-dione 382. Gut-chloro-19-fluoro-A -1Oa-pregnene-16a,17a-

dio'l-3,20-dione 383. 6a,19-dichloro-A -loa-pregnene-16a,17

dil-3,20-dione 384. 6a,19-difluoro-A -lOuregnene-16u,17e-diol- 3,20-dione 385. 6a-fiuor0-19-chloro-A -10a-pregnene-16a,17a-

diol-3,20-dione 386. 19-fiuoro-A -10a-pregnadiene-16u,17a-diol 3,20-dione 387. 19-chloro-A -l0a-pregnadiene-16u,17a-dio1 3,20-dione 388. 19-fiuoro-A -1Oaregnadicne-I6a,17e-diol- 3,20-dione 389. l9-chloro-A -IOaregnadiene-l6a,l7a-diol- 3,20-dione I 390. 19-fiuoro-A -IOaregnatriene160:,1711- diol-3,20-dione 391. 19-chloro-A -10a-preguatriene-16a, 1 7o:-

diol-3,20-dione Example XLVI A mixture of 1 g. of 19-fluoro-A -10a-pregnene-l6a,17- diol-3,20-dione (Cpd. No. 378), 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitatewas filtered, washed with water and dried. Crystallization from acetone-hexane gave the 16-acetate of 19- fluoro-A 10a-pregnene-16a,17a-diol-3,20-dione (Cpd. No. 392).

The Compounds Nos. 379 to 391, inclusive, were treated by the same procedure thus yielding respectively-- Example XLVII The compounds Nos. 393 to 405, inclusive, were treated in accordance with Example XXXIX, thus affording the corresponding 17-acetates.

Example XLVIII 19-flnoro-A -10a-pregnene 16e,17a diol 3,20 dione (Cpd. No. 378) was treated following the procedure described in Example XXXIX, thus yielding 19-fiuoro-A IOe-pregnenel6a,17u-diol-3,20-dione diacetate (Cpd. No. 406).

Example XLIX A suspension of g. of 19-fluoro-A -l0a-pregnene-3,20- dione (Cpd. No. 225), in 37.5 cc. of anhydrous peroxidefree dioxane was treated with 6.0 cc. of freshly distilled ethyl orthoforrnate and 4.0 g. of p-toluenesulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes furv ther. 3.8 cc. of pyridine were added and then water. The

formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetonehexane afforded 19-fiuoro-3-ethoxy-A -10a-pregnadien- 20-one.

A mixture of 5 g. of the latter 3-ethoxy compound 2 g. of anhydrous sodium acetate and cc. of acetone was treated with 32 cc. of water and the solution was cooled to a temperature between 0 and 5 'C. There was then added 1.1 molar equivalents of N-chloro-succinirnide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C. for 30 minutes. It was then diluted with water, kept overnight at 0 C. and the precipitate formed was collected, washed with water, dried under vacuum and recrystallized from acetone thus giving 65 chloro-19-tiuoro-A -10a-pregnene-3,20-dione (Cpd. N0. 407).

The Compounds Nos. 226 to 238, inclusive, were treated following the same procedures, thus atfording respectively- Cpd. No:

408. 6,6-chloro-19-fiuoro-16u-methyl-A -10apregnene-3,20-dione 409. 619-chloro-l9-fiuoro-16fi-methy1-A -10apregnene-3,20-dione 410. 6 8-chloro-19-fiu0ro-16e,17a-is0propy1idenedioxy-A -10u-pregnene-3,ZO-dione 41 1 6,6-chloro-19-fiuoro-A -10a-pregnen-17aol -3,20-dione 412. fifi-chloro-l9-fiuoro-16a-methyl-A -10apregnen-17a-o1-3,20-dione 413. 6fi-chloro-19-fiuoro-16fl-rnethyl-A -10apreguen-17a-ol-3,20-dione 414. 6a,19-dichloro-A -1Oa-pregnene-3,20-dione 415. 6;3,19-dichloro-16a-methyl-A -10apregnene-3,20-dione 416. 6fi,19-dichloro-16fl-methyl-A -10atpregnene-3,20-dione 417. 6B,19-dich1oro-l6u,17a-isopropylidenedioxy- A -10a-pregnene-3,20-dione 418. 618,19-dich1oro-A -IOe-pregnen- 17e-ol-3,20-dione 419. 6 8,19-dichloro-16e-methyl-A -lou-pregnen- 17ot-Ol-3,20-di0118 420. 6B,19-dichloro-16fl-methyl-A -IOeregnen- 17a-ol-3,20-dione Example L A suspension of 1 g. of 19-fiuoro-A -10u-pregnene-3,20- dione (Cpd. No. 225) in 7.5 cc. of anhydrous peroxidefree dioxane was treated with 1.2 cc. of freshly distilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 0.8 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetonehexane afforded 19-fluoro-3-ethoxy-A -10e-prcgnadiene- 20-one.

1 g. of the latter steroid was dissolved in 25 cc. of dimethylformamide. The solution was cooled to 0 C. and a stream of perchloryl fluoride was passed for 3 minutes; the solution was allowed to come slowly to 20 C.; it was then poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, then with water to neutrality, dried over anhydrous sodium sulfate, and evapduced orated to dryness. By chromatography over washed alumina there was produced 6p,19-difluoro-A -10a-preg- Cpd. No:

422. 6 8,19-difluoro-16a-methyl-A -10apregnene-3,20-dione ,424. 6 3,19-difluoro-16a,17u-isopropylidenedioxy- A -10a-pregnene-3,20-dione 425. 6/3,19-difluoro-A -10a-pregnen-17a-ol- 3,20-dione 426. 6fl,19-.difluoro-16a-methyl-A -lOu-pregnenl7a-ol-3,20-dione 427. 6fi,l9-difluoro-16fi-methyl-A -10a-pregnen- 17a-ol-3,20-dione 428. 6B fluoro-19-chloro-A -1Oa-pregnene- 3,20-dione 429. 6 8-fluoro-19-chloro-16e-methylA -10apregnene-3,20-dione 430. 6fl-fluoroe19-chloro-16 8-methyl-A -10apregnene-3,20-dione 431. 6fi-fluoro-19-chloro-l6a,17a-isopropylidenedioxy-A -10a-pregnene-3,20-dione pregnen-17a-ol-3,20-dione 434. op-fluoro-19-chloro-16p-methyl-A -10apregnen-17a-ol-3,20 dione Example LI To a solution of 20 cc. of 4 N methylmagnesium bromide in ether was added, with stirring, a solution of 2 g. of 3,20-bis-cycloethylenedioxy-5a,6a-oxido-19*fluoro-10apregnane (Cpd. No. 253) in 60 cc. of dry tetrahydrofuran and the stirred mixture heated under reflux for 30 minutes. The condenser was then replaced by a calcium chloride tube, the ether allowed to boil off and when the internal temperature reached 54 C., the condenser was readapted and the mixture refluxed for an additional 4 hours. 400 cc. of a saturated solution of ammonium chloride was added slowly to the cooled mixture which was then stirred for 15 minutes before transfer to a separatory funnel. The tetrahydrofuran layer was separated, dried, and evaporated to dryness.

A solution of the above residue in 70 cc. of methanol and 7 cc. of 8% aqueous sulfuric acid was refluxed for 40 minutes. It was then neutralized with saturated sodium carbonate solution, concentrated to ca. 20 cc. in vacuo and poured into water. The formed precipitate was filtered off and washed thoroughly with water and air dried.

A solution of the dry precipitate, 7 cc. of dry pyridine was cooled to 10 C., treated with 0.4 cc. of thionyl chloride and the mixture allowed to stand for 4 minutes at this temperature. Ice-water was added and the crystalline precipitate was filtered, washed and dried, yielding 19-fluoro-6fi-methyl-A -la-pregnene 3,20 dione (Cpd. No. 435).

The Compounds Nos. 254 to 266, inclusive, were treated by the above method, thus furnishing respectively-- Cpd. No.:

43 6. 19-fluoro-6B, l 6a-dimethyl-A 1 (la-pregnene- 3,20-dione 437. 19-fiuoro-6fi,16,9-dimethyl-A -IOwpregnene- 3,20-dione 438. 19-fluoro-6/3-methyl-16a,17a-isopropylidenedioxy-A -lOa-pregnene-3,20-dione 442. 19-chloro-6Bmethyl-A -l0a-pregnene-3,20-

dione 443. l9-chloro-6fi,16a-dimethyl-A -1Oa-Pregnene- 3,20-dione 444. 19-ch1oro-6fi,16B-dimethyl-A -IOuregnene- 3,20-dione 445. 19-chloro-6B-methyl-16a,17a-isopropylidenedioxy-A -10a-pregnene-3,20dione 446. 19-chloro-6fi-methyl-A -10a-pregnen 17aol-3,20-dione 447. 19-chloro-6B,l6a-dimethyl-A -IOa-pregnen- 17a-ol-3,20-dione 448. 19-chloro-6p,16fl-dimethyl-A -lOa-pregnenl7a-ol-3,20-dione Example LII The Compounds Nos. 407 to 448, inclusive, were treated following the procedure described in Example XXXIII thus affording the respective A -derivatives.

Example LIIl A mixture of l g. of l9-fluoro-A -10u-pregnene-l6a, l7a-diol-3,20-dione (Cpd. No. 378), 50 cc. of freshly distilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1 hour. The resulting mixture was washed with sodium bicarbonate solution and with water to neutrality, then it was steam distilled and the product extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetonehexane yielded 19-fiuoro-A -10a-pregnene 16a,17a -diol- 3,20-dione-l6,l7-acetophenonide (Cpd. No. 449).

The Compounds Nos. 379 to 391, inclusive, were treated following the aboveprocedure, thus affording the corresponding 16, l7-acetophenonides.

Example LIV Example LV Into a solution of 3 g. of Compound No.421 in cc. of glacial acetic acid was passed a slow stream of dry hydrogen chloride for 4 hours, while maintaining the temperature around 15 C. The mixture was then poured into ice-water, the precipitate collected, washed with water, dried and recrystallized from acetone-hexane to give a compound identical with Compound No. 295.

Example LVI A mixture of l g. of l9-fluoro-A -pregnene-16a,17adiol-3,20-dione (Cpd. No. 154) 50 cc. of freshly distilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1 hour. The resulting mixture was washed with sodium bicarbonate solution and with water to neutrality, then it was steam distilled and the product extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hex- 29 ane yielded 19-fiuoro-A -pregnene-l6a,17a-diol-3,2O-dione 16, 17-acetophenonide (Cpd. No. 451).

The Compounds Nos. 155 to 167, inclusive, were treated following the above procedure, thus affording the corresponding 16,17-acetophenonides.

Example LVII A solution of 500 mg. of compound No. 154 in 20 cc. of chloroform was treated with 1 g. of acetaldehyde and a few drops of 3 N perchloric acid and stirred at room temperature for 2 hours. After diluting with water the chloroform layer was separated, washed with aqueous saturated sodiumrbicarbonate solution and then with water, the chloroform was distilled and the residue was purified bychromatography on neutral alumina, thus yielding 16a,17m ethylidenedioxy-IQ-fluoIO-A -pregnene- 3,20-dione (Cpd. No. 452).

The Compounds Nos. 155 to 167, inclusive, were treated according to the latter procedure, thus furnishing the corresponding 16e,17a-ethylidenedioxy derivatives.

I claim: I

1. A compound of the following formula -R .x i T w i wherein R is selected from the group consisting of by drogen, hydroxyl and a hydrocarbon carboxylic group of less than 12 carbon atoms; T is a member of the group consisting of hydrogen, a-hydroxyl, tat-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms, a-methyl and fi-methyl; T and R together represent the. group wherein R and R are selected from the group consisting of hydrogen and a lower hydrocarbon residue of up to 8 carbon atoms; X is selected from the group consisting of fluorine and chlorine; Z is a member of the group consisting of hydrogen, a-methyl, p-methyl, m-fluorine, fi-fluorine, a-chlorine and B-chlorine; and W is selected from the group consisting of a saturated linkage between 0-1 and C-2 and a double bond between C-1 and C-2. 2. A compound of the following formula:

*2: w t Ii ,1)

wherein R is selected from the group consisting of hygen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T is a member of the group consisting of hydrogen, u-hydroxyl, u-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms, 6!-

methyl and fi-methyl;

T and R together represent the group i wherein R is selected from the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T is a member of the group consisting-of hydrogen, a-hydroxyl, tat-hydrocarbon carboxylic acyloxy of less than -12 carbon atoms, amethyl and B-methyl; T and R'together represent the group wherein R and R are selected fromthe group consisting of hydrogen and a lower-hydrocarbon residue or up to 8 carbon atoms; X is selected from the group con sisting of fluorine and chlorine; Z is a member of the group consisting of hydrogen, amethyl, B-methyl, afiuorine, ,B-fiuorine, a-chlorine and fi-chlorine; and W is selected from the groupconsisting of-a saturated linkage between 0-1 and C-2 and a double bond between 0-1 and C-2.

4. A compound of the following formula:

. Z wherein R is selected from the group consisting of hy-' drogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T is a member of the group consisting of hydrogen, d-hydroxyl, .a-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms, mmethyl and B-methyl; T and R together represent the group wherein R and R are selected from the group consisting of hydrogen and a lower hydrocarbon residue of up to 8 carbon atoms; X is selected from the group consisting of fluorine and chlorine; Z is' a member of the group consisting of hydrogen, methyl, fluorine and chlorine and W is selected from the group' consisting of a saturated linkage between C-1 and C-2 and a double bond between C-1 and C-2.

5. l9-halo-A -10a-pregnene-3,20-dione wherein halo is a halogen of atomic weight less than 36.

6. 6a-chloro-19-halo A -10a pregnene 3,20 dione wherein halo is a halogen of atomic weight less than 36. "7. 6d chloro 19-fiuoro-16-methyl-A -10a-pregnene- 3,20-dione. g

8. 60:,19 dichloro l6-methyl-A -10a-pregnene-3,2O- dione. v

9. l9-halo 16 methyl-A -10a-pregnene-3,20-dione wherein halo is a halogen of atomic weight less than 36.

10. 19-halo 16a,17a isopropylidenedioxy-M-10apregnene-3,20-dione wherein halo is a halogen of atomic weight less than 36. r

11. 19 halo A IOa-pregtwn-I'Ia ol-3,20-dione wherein halo is a halogen of atomic weight less than 36.

12. 1'9 halo-l6 methyl-A -10a-pregnen-l7a-ol-3,20- dione wherein halo is a halogen of atomic weight less than 36.

13. l9halo-A -pregnene-3,20-dionewherein halo' is a halogen of atomic weight less than 36.

14. 6a-chloro-19-halo-A -pregnene-3,20-dione wherein halo is a halogen of atomic weight less than 36.

15. 6a-chloro-19-fluoro 16-methyl-A pregnene-3,20- dione.

1-6. 6a,19-dichloro-1fi-methyl-A -pregnene-3,ZO-dione.

17. 19-halo 16-methyl A -pregnene-3,20 dione, wherein halo is a halogen of atomic weight less than 36.

18. 19-halo 16a,17a isopropylidenedioxy-M-pregnene-3,20-dione wherein halo is a halogen of atomic weight less than 36.

19. 19-halo-A -pregnene-l7a-ol-3,20 dione wherein halo is a halogen of atomic weight less than 36.

20. 19-halo 16-methyl-A -pregnen l7a-ol-3,20-dione wherein halo is a halogen of atomic weight less than 36.

References Cited by the Examiner UNITED STATES PATENTS 3,053,858 9/62 Mills 260-397.3

LEWIS GOTTS, Primary Examiner. 

3. A COMPOUND OF THE FOLLOWING FORMUAL: 